Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Research Institute, Beijing, China.
Fudan University Shanghai Cancer Center, Shanghai, China.
BMC Med. 2023 Jan 4;21(1):2. doi: 10.1186/s12916-022-02669-7.
HL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations.
This was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5-18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D.
Between September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade ≥ 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months.
The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations.
Trial registration ClinicalTrials.gov number: NCT03973151.
HL-085 是一种选择性的、口服给药的 MEK1/2 抑制剂。我们旨在评估 HL-085 用于携带 NRAS 突变的晚期黑色素瘤患者的安全性和疗效。
这是一项多中心的 1 期研究。HL-085 采用标准的 3+3 剂量递增设计（10 个剂量组；每日两次 0.5-18mg）进行给药，随后在推荐的 2 期剂量（RP2D）下进行剂量扩展。主要终点包括耐受性、剂量限制性毒性（DLT）、最大耐受剂量（MTD）和 RP2D。
2017 年 9 月 13 日至 2021 年 1 月 18 日期间，共纳入 42 例患者（剂量递增阶段：n=30；剂量扩展阶段：n=12）。在剂量递增期间未报告 DLT，HL-085 剂量高达每日两次 18mg 时未达到 MTD。RP2D 为每日两次 12mg。所有剂量水平下最常见的所有级别与药物相关的不良事件（AE）是皮疹（61.9%）、肌酸磷酸激酶（CK）升高（59.5%）、面部水肿（50.0%）、天门冬氨酸氨基转移酶（AST）升高（47.6%）、外周水肿（40.5%）、腹泻（33.3%）、丙氨酸氨基转移酶（ALT）升高（33.3%）和甲床炎（19.0%），大多数为 1 级和 2 级。最常见的 3 级及以上 AE 是 CK（14.2%）、乏力（7.1%）、外周水肿（4.8%）和痤疮样皮炎（4.8%）。在每日两次 12mg 剂量组（15 例患者）中，确认的客观缓解率为 26.7%；疾病控制率为 86.7%；中位缓解持续时间为 2.9 个月；中位无进展生存期为 3.6 个月。
HL-085 用于携带 NRAS 突变的晚期黑色素瘤患者，具有可接受的耐受性和显著的临床疗效。
临床试验.gov 编号：NCT03973151。
